Deciphering the selective estrogen receptor modulators (SERMS)
Goals of lecture: Tx Osteoporosis, reduce breast ca in post menopausal women.
20 years ago, early detection was as best as we could do.
SERM – noticed in mid 1980’s to switch on and off target sites for estrogen around the body.
2 SERMs today.
1. Tamoxifen – simple structure, stimulates uterus to grow, increase endometrial cancer, tx breast cancer, is sold under the trade names Nolvadex, Istubal, and Valodex
2. Toremifene citrate, Acapodene – tx breast cancer
3. Reloxifen - much improved, less able to stimulate uterus to grow, anti estrogenic. Does not increase endometrial cancer, tx for prevention osteoporosis, and breast cancer risk reduction. Evista
4. Clomiphene citrate is marketed under various trade names including Clomid, Serophene, Milophene, etc. Used for annovulation.
Normal phsyio of bone
Normal women before menopause – balance between bone resorption (osteoclastic cells that destroy bone) and bone formation(osteoblastic cells).
Chemical coupounds that are released from osteoblasts are 1. Stimulator, receptor activator of NF-κB ligand (RANKL) that turns on osteoclasts. Inhibitor protein that is released by osteoblasts called OPG(Osteoprotegerin (OPG), a soluble decoy receptor produced by osteoblasts, marrow stromal cells, and other cells, profoundly modifies the effects of RANKL by inhibiting RANKL/RANK interaction).
OPG slows down bone turnover by inhibiting RANKL.
In the presence of estrogen, tendency for bone preservation.
In the absence of estrogen by menopause, RANK ligand increases – more bone loss, and OPG diminishes.
SERMS act like estrogen.
1. Reversal of bone turnover process(rise in OPG(inhibitor) and decrease in RANK(activator)).
2. Restore bone physiology.
What does SERMS do?
Prevent bone loss and enhance bone maintainence.
Measuring activity by bone turnover marker.
Urine and blood measure collegen breakdown – alkaline phosphotase???
Chemical tests normalize within 1-3 months of use above drugs. Can see if pt does use it.
Preventative meds to preserve the bone at the time of drug initiation.
The earlier you use, the better you preserve the bone.
Safety issues??
1. Not incorporated into bone. Action is via interaction with cell receptors. As long as drug is present it works and as long as pt comes off the drug, interaction disappears in weeks and months.
2. No long term residence in the bone unlike some other drugs that tx osteoporosis.
Steps in evaluating the risk of breast cancer in postmenopausal women.
1. Did pt have previous breast cancer?
2. Previous Lobular carcino situ, atypical hyperplasia?? Increased risk substantially.
3. Gail model..age, f/hx, bx, and GY hx including age of menarche.
Small trials
1. Pilot trials britan
2. Italian study
3 large trials
1. Breast cancer study in US-2/3 postmenopausal – breast ca. Reduction with tamoxifen 49% decrease.
2. IBS 1 study in Great britan. Similar to Gail model. 34% reduction in risk. Fewer atypical/lobular cancer patients.
3. Star trial (Study of Tamoxifen and Reloxifen) –Reloxifen decreased large scale of breast cancer.
What is appropriate use of Tamoxifen or reloxifen.
1. Reloxifen – studied in post menopausal only and approved for only breast cancer reduction.
2. Tomxifen – Pre menopausal.
Efficacy is same.
Toxicity – no adverse uterine effect from Reloxifen. Thromboembolic event 30% lower in DVT and PE in reloxifen compared to tomaxifen.
Risks must fully be disclosed to the patient. Pt must understand that there is increased risk of uterine and thrombosis in tomaxifen.
Women >60, increased risk by age alone.
Lobular – Gail not need to be used.
Future direction of SERMS.
1. Develop drug in specific specificity. Nerve receptor that subdue hot flashes.
2. Drugs that have greater specificity to turn on inhibitors for osteoclastic activity and less resorptive activity.
3. Third generation SERMS – decrease even more breast can risk and tx better osteoporosis with less thrombogenic effect and no uterine problem.
Particular problems
Just come through menopausal
Perimenopausal – mood swings, sleep disturbance, needing hormone replacement therapy, particulary women who just stopped hormone after menopausal..
Do not SERM right away with pt who just had a postmenopausal due to increased sx.
Do hormone replacement therapy first followed by SERMS.
Worsening of menopausal such as vaginal dryness. Sx will abate with time.
5-7% will stop. But with appropriate info, and motivation, pt may stay with SERMS.
What is Gail Model?
The risk of developing an invasive breast cancer over the next five years and your lifetime probability of developing breast cancer can be calculated using a program called the Gail Model which has been validated in several studies. The Gail model takes into account five factors including your current age, age when you started menstruating (menarche), previous breast biopsies- -also taking into account if any of those biopsies demonstrated atypical growth, age at first live birth, family history of breast cancer in first-degree relatives. One of the disadvantages of this model is that it doesn't take into account age at which a family member was diagnosed and whether the disease occurred in both breasts -- early onset and bilateral disease suggests a BRCA mutation carrier.
If the Gail model predicts a 5-year risk of 1.66% or greater, you should consider discussing the STAR trial (if you are post-menopausal,) or possibly tamoxifen with your doctor. This entails a balanced discussion of the risks and benefits of these interventions- keeping in mind that nothing is without risk !! The Gail model doesn't apply to women with LCIS (lobular ca-in-situ), DCIS or if you have had a previous breast cancer. Remember the Gail Model assesses the probability of developing breast cancer, not dying from it !
